The present invention relates to the use of pramipexole or 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzo-thiazole, or the (+)- or (xe2x88x92)-enantiomers thereof, and the pharmacologically acceptable salts thereof, as a neuroprotective agent.
A number of central nervous system diseases and conditions result in neuronal damage. These conditions which can lead to nerve damage include:
Primary neurodegenerative disease; Huntington""s Chorea; Stroke and other hypoxic or ischemic processes; neurotrauma; metabolically induced neurological damage; sequelae from cerebral seizures; hemorrhagic stroke; secondary neuro-degenerative disease (metabolic or toxic); Parkinson""s disease; Alzheimer""s disease, Senile Dementia of Alzheimer""s Type (SDAT); age associated cognitive dysfunctions; or vascular dementia, multi-infarct dementia, Lewy body dementia, or neurodegenerative dementia.
Pramipexole is a dopamine-D3/D2 agonist the synthesis of which is described in European Patent 186 087 and its counterpart, U.S. Pat. No. 4,886,812. It is known primarily for the treatment of schizophrenia and Parkinson""s disease. It is known from German patent application DE 38 43 227 that pramipexole lowers the plasma level of prolactin. Also, this European patent application discloses the use of pramipexole in the treatment of drug dependency. Further, it is known from German patent application DE 39 33 738 that pramipexole can be used to decrease abnormal high levels of thyroid stimulating hormone (TSH). U.S. Pat. No. 5,112,842 discloses the transdermal administration of the compounds and transdermal systems containing these active compounds. WO patent application PCT/EP 93/03389 describes the use of pramipexole as an antidepressant agent.
Up to now there is no commercially available drug for the therapeutic treatment of stroke with proven evidence of efficacy.
Surprisingly and unexpectedly, it has been found that pramipexole and its (+)-enantiomer also has a neuroprotective effect.
Piribedil, a vasodilator which binds to a multitude of receptors including dopamine receptors, is reported to have an effect on functional and biochemical parameters in a gerbil model of global cerebral ischemia. See, e.g., Society for Neuroscience Abstracts, 19:673 (1993); id., at 1645.
Lisuride binds to several different receptors including dopamine D2 and 5-HT1a receptors. It is reported that Lisuride, when administered before the event, reduced brain edema and prolonged survival time in a rat model of cerebral infarction. Miya Zawa, et al. Nippon-Yakurigaku-Zasshi 98(6):449-561, (1991).
The present invention particularly provides a method for preventing neuronal damage in a patient suffering from or susceptible to such neuronal damage comprising the administration of an effective amount of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole, its (xe2x88x92)-enantiomer or (+) -enantiomer thereof, and pharmacologically acceptable salts thereof especially an effective amount of pramipexole which is the (xe2x88x92)-enantiomer of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole-dihydrochloride or an effective amount of the (+)-enantiomer of 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole dihydrochloride.
Conditions which can cause nerve damage are well-known to an ordinarily skilled neurologist or similar physician and include:
Primary neurogenerative disease;
Huntington""s Chorea;
Stroke and other hypoxic or ischemic processes;
Neurotrauma;
Metabolically induced neurological damage;
Sequelae from cerebral seizures;
Hemorrhagic stroke;
Secondary neurodegenerative disease (metabolic or toxic);
Parkinson""s disease;
Alzheimer""s disease, other memory disorders; or
Vascular dementia, multi-infarct dementia, Lewy body dementia, or neurogenerative dementia.
The preferred indication for pramipexole, in the context of the present invention, is Parkinson""s disease which is characterized by progressive degeneration of nigrostriatal dopamine neurons. In this sense, the term Parkinson""s disease also comprises the term Parkinson""s syndrome. In addition to pramipexole""s palliative action (i.e. replacement of the lost dopamine neurotransmitter function), the compound may slow the degeneration of surviving dopamine neurons and thereby slows the progression of the disease.
The prophylactic use of the compound of this invention includes use as monotherapy in early or pre-symptomatic stages of Parkinson""s disease and prevention of neurodegenerative disorders based on ischaemia.
The synthesis, formulation and administration of pramipexole is described in U.S. Pat. Nos. 4,843,086; 4,886,812; and 5,112,842; which are incorporated by reference herein.
2-Amino-6-n-propyl-amino-4,5,6,7-tetrahydrobenzothiazole, particularly the (xe2x88x92)-enantiomer thereof, and the pharmacologically acceptable acid addition salts thereof can be given for preventing of neuronal damage. The form of conventional galenic preparations consist essentially of an inert pharmaceutical carrier and an effective dose of the active substance; e.g., plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, etc.
L-dopa is shown to be toxic to cerebellar granule cells in culture. Pramipexole and the (+) enantiomer blocked L-dopa toxicity. The EC50for both was between 0.3 and 1 uM and 10 uM provided viability measurements that were equal to control cells not exposed to L-dopa. The mechanism of protection does not appear to involve receptor activation given that the (+) enantiomer is less active in monoamine receptor binding assays. The possibility exists that 2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzothiazole, its (+) and (xe2x88x92) enantiomers and the pharmacologically acceptable acid addition salts thereof, especially pramipexole and the (+) enantiomer are acting as antioxidants toward reactive oxygen species known to be generated from L-dopa incubation.
The effective dose range is 0.01 to 2.0 mg/kg. More preferred is a dose of 1-2 mg/kg PO. The preferred total dose level for neuroprotection is 0.5-20 mg/kg/day PO. The preferred human dose is 0.1-6.0 mg/day total dose, divided in 2 or 3 administrations. In addition to being administered by oral or intravenous route, pramipexole may be administered transdermally.